Recent data suggest that progressive dementia occurs in some 20-50% of brain tumor patients who are long-term survivors after treatment with brain irradiation. The need to both understand and minimize the side effects of brain irradiation is exacerbated by the ever-increasing number of patients with secondary brain metastases that require treatment with large field or whole brain irradiation (WBI); some 175,000-cancer patients/year receive large field or WBI. At the present time, there are no successful treatments for radiation-induced brain injury, or are there any known effective preventive strategies. Data support a role for acute and chronic inflammation and/or oxidative stress in radiation-induced brain injury. Peroxisomal proliferator-activated receptors (PPARs) are members of the nuclear hormone receptor superfamily of ligand-activated transcription factors. A growing body of evidence suggests an anti-inflammatory/ protective role for PPAR agonists in the CNS. We hypothesize that activation of PPARalpha and/or PPARgamma will ameliorate the development and progression of radiation-induced brain injury, including cognitive impairment. To test this hypothesis, we will pursue the following Specific Aims. Using well-defined in vitro models of rat astrocytes and rat brain microvascular endothelial cells (RBMECs), we will determine if: 1] pre-incubating normal brain cells with PPARalpha and/or PPARgamma agonists prior to treatment with radiation or other reactive oxygen species (ROS) can inhibit the pro-inflammatory response and upregulation of redox-regulated gene products; 2] inhibiting and enhancing PPARalpha and PPARgamma activation using pharmacological inhibitors and gene-transfer approaches will prevent and enhance, respectively, the PPAR-induced modulation of rat astrocyte and RBMEC phenotype observed following treatment with radiation and other ROS generating stimuli. We will test the in vivo significance of these in vitro observations by pursuing the following Specific Aims: 1] we will determine if chronic administration of PPARalpha or PPARgamma agonists will reduce the severity of radiation-induced brain injury, including cognitive dysfunction; 2] we will use PPARalpha KO mice, and conditional PPARgamma KO mice in which PPARgamma expression will be knocked out either in astrocytes or in endothelial cells, to test the hypothesis that knocking out PPARalpha or PPARgamma will lead to increased radiation-induced brain injury. Establishment of a pathogenic role for PPARs in radiation-induced brain injury offers the promise of increasing the therapeutic window for cancer patients receiving brain irradiation and positively impacting both their quality of life and long-term survival.